Vagal nerve stimulation techniques for treatment of epileptic seizures

ABSTRACT

The present invention uses electrical stimulation of the vagus nerve to treat epilepsy with minimized or no effect on the heart. Treatment is carried out by an implantable signal generator, one or more implantable electrodes for electrically stimulating a predetermined stimulation site of the vagus nerve, and a sensor for sensing characteristics of the heart such as heart rate. The heart rate information from the sensor can be used to determine whether the vagus nerve stimulation is adversely affecting the heart. Once threshold parameters are met, the vagus nerve stimulation may be stopped or adjusted. In an alternative embodiment, the invention may include a modified pacemaker to maintain the heart in desired conditions during the vagus nerve stimulation. In yet another embodiment, the invention may be simply a modified pacemaker having circuitry that determines whether a vagus nerve is being stimulated. In the event that the vagus nerve is being stimulated, the modified pacemaker may control the heart to maintain it within desired conditions during the vagus nerve stimulation.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 10/712,975, filed Nov. 13, 2003, now U.S. Pat. No. 6,961,618,which is a continuation of U.S. patent application Ser. No. 10/053,425,filed Nov. 9, 2001, now U.S. Pat. No. 6,671,556 which is a continuationof U.S. patent application Ser. No. 09/302,516, filed Apr. 30, 1999, nowU.S. Pat. No. 6,341,236 for which priority is claimed. These parentapplications are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

This invention relates to neural tissue stimulation techniques, and moreparticularly relates to techniques for providing more effective vagusnerve stimulation and for controlling or preventing epileptic seizureswith minimized effect on the heart.

BACKGROUND OF THE INVENTION

Epileptic seizures are the outward manifestation of excessive and/orhypersynchronous abnormal activity of neurons in the cerebral cortex.Many types of seizures occur. The behavioral features of a seizurereflect function of the portion of the cortex where the hyper activityis occurring. Seizures can be generalized and appearing to involve theentire brain simultaneously. Generalized seizures can result in the lossof conscious awareness only and are then called absence seizures(previously referred to as “petit mal”). Alternatively, the generalizedseizure may result in a convulsion with tonic-clonic contractions of themuscles (“grand mal” seizure). Some types of seizures, partial seizures,begin in one part of the brain and remain local. The person may remainconscious throughout the seizure. If the person loses awareness, theseizure is referred to as a complex partial seizure.

A number of techniques are known to treat seizures including, forexample, drug therapy, drug infusion into the brain, electricalstimulation of the brain, electrical stimulation of the nervous system,and even lesioning of the brain. U.S. Pat. No. 5,713,923 entitledTechniques of Treating Epilepsy by Brain Stimulation and Drug Infusion”generally discloses such techniques in the background section andspecifically discloses techniques for drug infusion and/or electricalstimulation to treat epilepsy. This patent is incorporated herein byreference in its entirety.

U.S. Pat. No. 5,025,807 entitled “Neurocybemetic Prosthesis” and itsparentage (U.S. Pat. Nos. 4,867,164 and 4,702,254) (all three patentsare collectively referred to herein as the “Zabara patents”) disclosetechniques for electrical stimulation of the vagus nerve. These Zabarapatents generally disclose a circuit-based device that is implanted nearthe axilla of a patient. Electrode leads are passed from the circuitdevice toward the neck and terminate in an electrode cuff or patch onthe vagus nerve.

The neuro-cybernetic prosthesis (NCP) is the primary vagus nervestimulation (VNS) system that is presently available. This presentlyavailable VNS treatment technique for the treatment of epilepsy,however, has limited therapeutic efficacy and exerts clear but variablechronotropic effects on the human heart. See Handforth et. al., “VagusNerve Stimulation Therapy for Partial Onset Seizures: A RandomizedActive Control Trial,” J. Neurology, Vol. 51, pp. 48-55 (1998); Han etal, “Probable Mechanisms of Action of Vagus Nerve Stimulation in Humanswith Epilepsy: Is the Heart the Window into the Brain?” AES Proceedings,p. 83 (1997); Frei et al., “Effects of Vagal Stimulation on Human EEG,”AES Poceedings, p. 200 (1998) (each of these references are incorporatedherein by reference in their entireties). With regard to the heart,vagus nerve stimulation has the side-effect of altering the heart rate.See Frei et al. “Effects of Vagal Stimulation on Human ECG,” Abstractfrom the Annual Meeting of the American Epilepsy Society, Vol. 39, Supp.6 (1998), which is incorporated herein by reference in its entirety.Typically, activation of the device and stimulation of the vagus nervecauses the heart to experience a significant drop in heart rate. Forexample, FIG. 1A is graph illustrating the effects of vagus nervestimulation on the heart rate for a patient. In this Figure, thehorizontal axis represents time and the vertical axis represents thenormalized heart rate. A value of 1 in this graph indicates that theinstantaneous heart rate (IHR) at that point in time is equal to themedian IHR for the current vagus nerve stimulator (VNS) device cycle(i.e., for the current 5½ minute window). The graph shows that duringvagus nerve stimulation from time 0 to 50, the heart rate drops to aslow as 0.8 of its background rate. Similarly, FIG. 1B is a graph of theinstantaneous heart rates (defined herein) of a patient as a function oftime over an 8 hour period. The sharp drops that occur periodicallyalong the bottom of the graphed line correspond to times when the vagusnerve stimulation device is reset or turned “on”. These sharp dropsillustrate the effect that vagus nerve stimulation has on the heart.Notably, the Zabara patents recognize that the heart rate slows as aresult of the stimulation. This effect that vagus nerve stimulation hason the heart is undesirable due to negative short- or long-term effectson the patient. For example, the heart may become less adaptable tostresses due to the vagus nerve stimulation, which may lead toarrhythmia, asystole (heart stoppage), and possibly even to suddendeath. See Asconape et al, “Early Experience with Vagus NerveStimulation for the Treatment of Epilepsy; Cardiac Complications, AESProceedings, p. 193 (1998) (incorporated herein by reference in itsentirety).

The relative lack of efficacy and the adverse effects of the VNS areattributable in part to inadequate stimulation. Specifically, the NCPdoes not change the electro-encephalogram (EEG) reading. See Salinsky etal. “Vagus Nerve Stimulation Has No Effect on Awage EEG Rythms inHumans,” J. Epilespia, Vol. 34 (2), p. 299-304 (1993). Adequatestimulation of the vagus nerve induces either synchronization ordesynchronization of brain rhythms depending on the stimulationparameters used. See Michael H. Chase et al., “Afferent VagalStimulation: Neurographic Correlates of Induced EEG Synchronization andDesynchronization,” Brain Research pp. 236-249 (1967); Chase et al,“Cotical and Subcortical Patterns of Response to Afferent VagulStimulation,” Experimental Neurology, Vol. 16, pp. 36-49 (1966). EEGdesynchronization requires selective activation of slow conducting nervefibers. This state of desynchronization does not favor the occurrence ofseizures and is therefore preferred for this specific therapeuticpurpose. The absence of EEG changes in humans during VNS suggestsstimulation is inadequate and this in turn may explain its relativelylow therapeutic value. See Handforth et. al., “Vagus Nerve StimulationTherapy for Partial Onset Seizures: A Randomized Active Control Trial,”J. Neurology, Vol. 51, pp. 48-55 (1998).

In addition, VNS provides non-selective bi-directional nerve fiberactivation. In general, the VNS stimulation affects the brain (adesirable target) and also the viscera, including the heart (undesirabletargets). Accordingly, VNS causes alterations in the heartelectrocardiogram (EKG) reading. Given the shape of the pulse, itsbiphasic nature and the intensity settings available in the NCP,selective stimulation of slow conducting nerve fibers (a necessarycondition for EEG desynchronization) is highly unlikely with thisdevice.

Further, the NCP provides indiscriminate timing for stimulation of theheart. Cardiac arrest can result from stimulation of the heart duringvulnerable phases of its cycle. See Jalife J, Anzelevitch C., “Phaseresetting and annihilation of pacemaker activity in cardiac tissue,”Science 206:695-697 (1979); Jalife J, Anzelevitch C., “Pacemakerannihilation: diagnostic and therapeutic implications,” Am. Heart J.100:128-130 (1980); and Winfree A T., “Sudden Cardiac Death: A Problemin Topology,” Sci Am 248:144-161 (1983). VNS can cause cardiac arrestbecause the timing of stimulation does not take into account the phaseor state of the cardiac cycle.

Accordingly, it is an object of the invention to provide a technique forcontrolling or preventing epilepsy via stimulation of the vagus nervewith minimized effect on the heart rate. It is another object of theinvention to provide a technique for adjusting the vagus nervestimulation to minimize its affect on the heart rate. It is anotherobject of the invention to provide stimulation of the vagus nerve whilemaintaining the heart rate at a preset rate. It is a further object tominimize the risk of cardiac arrest in patients receiving VNS bydelivering stimuli at times in the heart cycle which cause no or minimaladverse effects on rhythms generation or propagation. Other objects ofthe present invention will become apparent from the followingdisclosure.

BRIEF SUMMARY OF THE INVENTION

The present invention discloses techniques for treating epilepsy byproviding electrical stimulation of the vagus nerve to inducetherapeutic EEG changes with little or no potentially serious orlife-threatening side-effects, especially to the heart. Accordingly, thepresent invention discloses techniques for adjusting the vagus nervestimulation and/or controlling the heart rate during vagus nervestimulation to maintain the heart within desired parameters. In apreferred embodiment of the present invention, treatment is carried outby an implantable signal generator, one or more implantable electrodesfor electrically stimulating a predetermined stimulation site of thevagus nerve, and a sensor for sensing characteristics of the heart suchas heart rate. The heart rate information from the sensor can be used todetermine whether the vagus nerve stimulation is adversely affecting theheart. Once threshold parameters are met, the vagus nerve stimulationmay be stopped or adjusted. In an alternative embodiment, heart EKGsignals may be monitored and applied to an EKG algorithm to detectepileptic seizures and to responsively trigger the signal generator toprovide stimulation to the vagus nerve.

In an alternative embodiment, the invention may include a modifiedpacemaker to maintain the heart in desired conditions during the vagusnerve stimulation. In yet another embodiment, the invention may besimply a modified pacemaker having circuitry that determines whether avagus nerve is being stimulated. In the event that the vagus nerve isbeing stimulated, the modified pacemaker may control the heart tomaintain it within desired conditions during the vagus nervestimulation.

In yet another embodiment, EKG rhythms may be sensed so as to minimizeEKG changes via cybernetic techniques. In another embodiment, thepresent invention may selectively stimulate certain fiber groups withinthe vagus nerve to block the propagation of impulses towards theviscera, such as the heart, using electrophysiologic techniques. Instill another embodiment, the present invention may sense brain EEG toprovide feedback on the vagal nerve stimulation. Alternatively, heartEKG may be monitored to determine whether there is a risk of a possibleseizure onset to either adjust the VNS stimulation or to warn thepatient.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other advantages and features of the invention will becomeapparent upon reading the following detailed description and referringto the accompanying drawings in which like numbers refer to like partsthroughout and in which:

FIG. 1A is graph illustrating the effects of vagus nerve stimulation onthe heart rate for a patient.

FIG. 1B is a graph of the instantaneous heart rate of a patient as afunction of time over an 8 hour period.

FIG. 2 is a schematic block diagram of the components of the presentinvention implanted within a patient in accordance with a preferredembodiment of the present invention.

FIG. 3 is a block diagram depicting the connection between the sensorand the signal generator.

FIG. 4 is a schematic block diagram of a microprocessor and relatedcircuitry for utilizing the sensor to control stimulation administeredto the vagus nerve.

FIG. 5 is a graph of standard deviations of the instantaneous heart rate(IHR) of a patient as a function of the IHR.

FIG. 6 is a flow chart depicting a control algorithm utilized tominimize the effect of vagus nerve stimulation on the heart.

FIG. 7 is a graph depicting the IHR of a patient as a function of time.

FIG. 8 depicts another embodiment of the present invention having apacemaker or a like device implemented to affect the heart in the eventthat vagus nerve stimulation causes the heart to beat outside of theacceptable ranges.

FIG. 9 is a schematic diagram of yet another embodiment of the inventionwhere a pacemaker is modified with a digital signal processing algorithmto recognize whether the vagus nerve is being stimulated.

FIG. 10 is a block diagram of an algorithm for detecting whether a vagusnerve stimulator is stimulating the nerve based on heart EKG.

FIGS. 11A-C are graphs illustrating the EKG signal as it is processed bythe algorithm of FIG. 10.

FIGS. 12A-B are schematic diagrams of one or more electrode pairsproviding stimulation to the vagus nerve in accordance with anembodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Referring to FIG. 2, a system 10 made in accordance with a preferredembodiment may be implanted below the skin of a patient. System 10generally includes a sensor 15 for sensing a characteristic of the heart55 of the patient, a signal generator 20, and one or more stimulationelectrodes 25. System 10 may be a modified version of the devicesdisclosed in the Zabara patents and are incorporated herein byreference.

Sensor 15 is implemented at or near the heart 55 to sense acharacteristic of the heart 55, including the heart rate. A number oftechniques may be used to sense the heart rate including, but notlimited to, QRS detection or R-wave detection techniques, for example,as disclosed in Antti Ruha et al., “A Real-Time Microprocessor QRSDetector System with a 1-ms Timing Accuracy for the Measurement ofAmbulatory HRV,” IEEE Transactions on Biomedical Engineering, Vol. 44,No. 3, pp. 159-167 (March 1997). Another technique may use standardanalog techniques. In alternative embodiments, sensor 15 may bephysically located outside of the body and communicate with theimplanted portion through telemetry.

Sensor 15 is coupled to signal generator 20 via cable 17. Sensor 15 andsignal generator 20 may alternatively communicate via telemetry such as,for example, radio-frequency signals. Alternatively, sensor 15 andsignal generator 20 may be a single device that may be part of a heartpacemaking or like device. Depending upon the sensor 15 used, theoutputs of sensor 15 may require the use of an analog-to-digital (A/D)converter 18 to be coupled between sensor 15 and signal generator 20 asshown in FIG. 3. The output of A/D converter 18 is connected tomicroprocessor 200 as shown in FIG. 4. Alternatively, if an A/Dconverter 18 is not required, the output from sensor 15 can be filteredby an appropriate electronic filter 19 prior to delivery of the sensorsignal to signal generator 20.

When in operation to stimulate the vagus nerve 60, signal generator 20receives the sensed information from sensor 15 and adjusts thestimulation therapy in response to the sensed information in accordancewith the present invention. Signal generator 20 is preferably capable ofproviding a range of stimulation therapy with adjustable cyclingparameters of the electrical pulse including but not limited to pulseshape, inter-stimulus: interval, pulse frequency, pulse width, pulseamplitude, and pulse phase. As discussed herein, it is preferred thatthe stimulation be accomplished so as to have minimal effect on theheart. Continuous stimulation may also be provided. Preferably, signalgenerator 20 is of the type which is capable of ramping up to the setpulsing parameters whenever the signal generator 20 is activated. Thistechnique helps eliminate involuntary twitching when the prosthesis isactivated. Once implanted, signal generator 20 must be “tuned” toprovide desired treatment therapy to the specified nerve properties ofthe vagus nerve 60. Signal generator 20 accordingly is capable ofvarying before and after implant the pulsing parameters of the pulsesignal. After implant, the pulsing parameters may be adjustable viatelemetry which is known to those skilled in the art.

As shown in FIG. 3, signal generator 20 may include a microprocessor 200that is coupled to the output of A/D converter 18, filter 19 or directlyto sensor 15. Microprocessor 200 processes the sensor data in differentways depending on the type of transducer in use. Microprocessor 200 mayread the sensor signal and stores one or more values in RAM 102 a.Referring now to FIG. 4, memory 204 may be used to store parameters forcontrol of the stimulation therapy based on the sensor signal.Microprocessor 200 is coupled to a peripheral bus 202 having address,data and control lines. Stimulation is delivered through an outputdriver 224.

Signal generator 20 is suited to provided stimulation therapy withadjustable pulse frequency, pulse width and pulse amplitude. Thestimulus pulse frequency is controlled by programming a value to aprogrammable frequency generator 208 using bus 202. The programmablefrequency generator 208 provides an interrupt signal to microprocessor200 through an interrupt line 210 when each stimulus pulse is to begenerated. The frequency generator 208 may be implemented by modelCDP1878 sold by Harris Corporation. The amplitude for each stimuluspulse is programmed to a digital to analog converter 218 using bus 202.The analog output is conveyed through a conductor 220 to an outputdriver circuit 224 to control stimulus amplitude. Microprocessor 200also programs a pulse width control module 214 using bus 202. The pulsewidth control provides an enabling pulse of duration equal to the pulsewidth via a conductor 216. Pulses with the selected characteristics arethen delivered from signal generator 20 through cable 22 to theelectrodes 25 which are in communication with the vagus nerve 60.Electrical stimulation of the vagal nerve 60 may be implemented byproviding pulses to electrodes 25 having amplitudes of 0.1 to 20 volts,pulse widths varying from 0.02 to 1.5 milliseconds, and repetition ratesvarying from 2 to 2500 Hz. The appropriate stimulation pulses aregenerated by signal generator 20 based on the computer algorithm,parameters set by the clinician, and the features of the presentinvention.

Microprocessor 200 executes an algorithm to provide stimulation withclosed loop feedback control based on the sensed conditions of the heartfrom sensor 15. At the time the signal generator 20 is implanted, theclinician programs certain key parameters into the memory of theimplanted device via telemetry. These parameters may be updatedsubsequently as needed. Alternatively, the clinician may elect to usedefault values. The clinician must program the range of values for pulsewidth, amplitude and frequency which signal generator 20 may use tooptimize the therapy.

The stimulation may be applied continuously to prophylactically preventthe onset of seizures, manually by the patient, or it may turn on inresponse to a signal on secondary sensor 30 (discussed herein)indicating the beginning of a seizure. Stimulus parameters can beadjusted by the computer algorithm within a range specified by theclinician in an attempt to optimize the seizure suppression.

Signal generator 20 is implanted in a human body in a subclavicular,subcutaneous pocket. Signal generator 20 may also be implanted near theheart 55. For example, in one embodiment discussed herein, signalgenerator 20 may be encased along with sensor 15 near the heart 55.Signal generator 20 may take the form of a modified neuro-cyberneticprosthesis (NCP) device, a modified signal generator Model 7424manufactured by Medtronic, Inc. under the trademark Itrel II, or anyother signal generator suited for stimulation of the vagus nerve 60.Signal generator 20 may also be similar to one disclosed in the Zabarapatents, which are incorporated herein by reference, with themodification that it be adjustable and responsive to sensor 15.

Signal generator 20 is coupled to the proximal end of at least one lead22. The distal end of 22 terminates in one or more stimulationelectrodes 25 that can stimulate neurons in the vagus nerve 60. Theelectrodes 25 are shown as an electrode patch, which is generally knownin the art, though single electrodes may also be used. Various otherknown electrodes may also be used such as, for example, a tripolar cuffelectrode. The electrodes 25 may be of the form disclosed in the Zabarapatents and are incorporated herein by reference. Electrode patchesinclude both positive and negative electrodes. Electrodes 25 may beplaced anywhere along the length of the vagus nerve 60, above or belowthe inferior cardiac nerve depending upon the particular application.Electrodes 25 are placed on or near the vagus nerve 60 or in indirectcontact with the vagus nerve 60.

FIG. 12A shows an embodiment of the present invention having a pair ofelectrodes for use in different combinations. The electrode pair ispositioned to stimulate the vagus nerve 60. As preferred, the anode isimplanted to be closest to the heart so as to block passage of unwantednerve impulses towards the viscera, such as the heart. The pulse ispreferably a saw-tooth wave as shown as having a steeply risingbeginning followed by a slow exponential decay, although any other waymay be used. The outward flow of current at the cathode, triggersconducted impulses in larger and smaller nerve fibers while the inwardinflow at the anode inactivates the conduction of impulses in thesmaller or slower conduction fibers. The differential effect of anodalcurrents results form the greater internal conductances and greaterconduction velocity of larger (faster) conducting nerve fibers. SeeAccornero et al. “Selective Activation of Peripheral Nerve Fibre Groupsof Different Diameter by Triangular Shaped Pulses,” J. Physiol., pp.539-560 (1977). Simply stated, anodal currents causes a functional nerveblock.

Alternatively, a modification of the above technique may be implementedwhich rests on the Alaw of independent conduction@ of nerve fibers.Bures et al., “Electrophysiological Methods in Biological Research,”Academic Press New York, London, pp 338-339 (3rd ed. 1967). This lawgenerally states that larger fibers will conduct impulses faster thansmaller fibers. In this embodiment, impulses travelling in larger ormyelinated fibers will reach the anode well before the smaller or slowerconducting fibers and while the functional block is still active. SeeJones et al., “Heart rate responses to selective stimulation of cardiacvagal C fibers in anaesthetized cats, rats and rabbits,” J. Physiol(London) 489.1:203-214 (1995). These fast impulses which are more likelyto alter the heart than the slow conducting ones, will be prevented fromreaching the heart (Id.). The distance between the active electrodesshould be sufficiently long so as to allow the differential conductionof impulses to fully take place or develop. The optimal distance betweenthese electrodes can be found during the implantation procedure.

If the anodal current is maintained for a sufficiently long period oftime, the slow traveling impulses can be also blocked from reaching theheart. The duration of anodal stimulation necessary to attain thiseffect can be determined during the implantation procedure or at a latertime. Those skilled in the art understand that more than one pair ofelectrodes and different impulse shapes, phases and time constants maybe used to optimize blockage of impulses travelling towards the heartusing collision techniques. See Jones et al., “Heart rate responses toselective stimulation of cardiac vagal C fibers in anaesthetized cats,rats and rabbits,” J Physiol (London) 489.1:203-214 (1995). Electrodescan be used not only to transfer energy to the vagus nerve 60 but alsoto record its activity.

FIG. 12B discloses that two more electrode pairs may also be used withthe pair closest to the heart serving to guard against fast conductingfibers that may pass through to the heart. Again, each of the pairedelectrodes are configured so that the anode is closest to the heart. SeeJones et al., “Heart rate responses to selective stimulation of cardiacvagal C fibers in anaesthetized cats, rats and rabbits,” J Physiol(London) 489.1:203-214 (1995). The use of asymmetric shielded two orsingle electrode cuffs is described in U.S. Pat. Nos. 4,628,942 and4,649,936, which are incorporated herein by references in theirentireties. These electrodes were designed to allow unidirectionalspread and will be placed around the vagus nerve 60 in a manner whichwill ensure that impulses during stimulation will travel only in thedirection of the brain, ensuring maximal efficacy and minimal cardiacside effects.

As another option, high frequency (>100 Hz) stimulation of a portion ofthe nerve proximal to the heart may be implemented to prevent thetreatment stimulation from affecting the heart. This is desirable sincehigh frequency stimulation causes a functional block of the part of thenerve under stimulation.

It is optionally desirable to provide selective stimulation of the vagusnerve 60 based on fiber types and using various pulsing techniques toachieve unidirectional activation of action potentials. The fiber typesof the vagus nerve 60 may be selected in accordance with the techniquesdisclosed in U.S. Pat. No. 4,628,942 entitled Asymmetric Shielded TwoElectrode Cuff”; U.S. Pat. No. 4,649,936 entitled “Asymmetric SingleElectrode Cuff For Generation Of Unidirectionally Propagating ActionPotentials For Collision Blocking”; and Accornero et al. “SelectiveActivation of Peripheral Nerve Fibre Groups of Different Diameter byTriangular Shaped Pulses,” J. Physiol., pp. 539-560 (1977) all of whichare incorporated herein in their entireties. This will allow the effectsof the stimulation to reach the brain as desired while minimizing theeffects of the stimulation on the heart.

System 10 may include additional components including for example asecond sensor 30 implanted within the brain that provides closed-loopfeedback of sensed conditions indicative of a possible seizure onset.Second sensor 30 may be coupled to signal generator 20 in a mannersimilar to that depicted in FIG. 3. The Zabara patents disclose suchclosed-loop feedback systems and are incorporated herein by reference.U.S. Pat. No. 5,713,923 entitled “Techniques of Treating Epilepsy byBrain Stimulation and Drug Infusion” (“the '923 patent”) also disclosessuch techniques for closed-loop feedback control and the types ofsensors that can be used. The '923 patent is incorporated herein byreference in its entirety. System 10 may also be implemented as anopen-loop system where the patient may manually operate a switch to turn“on” and “off” the vagus nerve stimulation system 10 based on sensedaura indicative of a seizure onset. Even with a fully implanted device,a momentary contact switch, a magnetically operated reed switch, or anumber of other devices may be utilized to provide external control ofthe implanted device. Those skilled in the art will appreciate how toimplement such devices.

It is an object of the present invention to minimize or eliminate theeffects on the heart caused by the electrical stimulation of the vagusnerve 60. The techniques for achieving this are discussed herein, butreference to FIG. 5 is made for a more defined understanding of theproblem. FIG. 5 is a graph of standard deviations (SDT) of theinstantaneous heart rate (IHR) of a heart of a patient as a function ofthe IHR. The IHR is number of beats of the heart per minute at any giventime. IHR may be calculated by first measuring (in seconds) the timebetween two beats of the heart to derive the pulse rate or the beatinterval. IHR is then determined by dividing 60 by the beat interval.

Referring still to FIG. 5, the horizontal axis is the instantaneousheart rate (IHR) averaged for 5 consecutive beats and the vertical axisis the standard deviation of the IHR measurements for the same 5 beats.The dots or points on the graph represent the standard deviations of theIHR measurements as a function of the IHR during the time period whenthe vagus nerve stimulator (VNS) is off. The solid lines in the graphrepresent 10 percentile divisions with the darkest solid line being themedian standard deviation as a function of the IHR. As shown in thegraph of FIG. 5, there is an inverse proportion between the IHR and thestandard deviation, namely at lower IHR there is greater variability ofthe heart rate (higher standard deviation between IHRs) and as the heartbeats faster (higher IHR) there is less variability of the heart rate(lower standard deviation between IHRs). However, when the vagus nerve60 is electrically stimulated, this relationship changes as depicted bythe dashed lines in the graph (darkest dashed line being the medianstandard deviation as a function of the instantaneous heart rate). Theinventors have found that the relationship between the IHR and thestandard deviation between the IHRs is altered by electrical stimulationof the vagus nerve 60. Generally, stimulation of the vagus nerve 60increases heart rate variability (standard deviation) at higher IHRvalues. It is therefore desirable to provide a technique for vagus nervestimulation that minimizes or has no effect on the normal operation ofthe heart as measured by the standard deviation of the IHR as a functionof the IHR.

Vagus nerve stimulation may be adjusted or controlled based oninstantaneous heart rate (IHR) measurements and/or heart ratevariability. Those skilled in the art will recognize that other measuresof cardiac cycle lengths may alternatively be used besides IHR. Thefollowing control algorithm, with reference to FIG. 6, may be utilizedto minimize the effect of vagus nerve stimulation on the heart. At step605, sensor 15 can measure the pulse rate or beat interval in seconds.The beat interval is generally the time period between heart beats. Atstep 610, the instantaneous heart rate (IHR) is calculated, by dividing60 by the beat interval (i.e., 60/beat interval). At step 615, heartrate variability can optionally be measured depending upon how thefeedback is to be accomplished (discussed herein in further detail).Heart rate variability can be based on the IHR calculation using anynumber of techniques. A number of known systems exist for determiningheart rate variability, including by way of example, that disclosed inU.S. Pat. No. 5,330,508 which is incorporated herein by reference.However, these known are generally inapplicable as they require heartrate variability measurements over long intervals of time, typically 5minutes. As preferred, the present invention measures heart ratevariability based on much short time periods of IHR measurements,preferably 3 to 5 beat intervals. Those skilled in the art willappreciate that longer periods may be used to practice the invention.Heart rate variability may, for example, be taken by calculation of thestandard deviation of 5 IHR measurements (as illustrated in FIG. 5discussed above). Another way to measure heart rate variability is toestablish a statistical analysis of the heart rate variabilities basedon past IHR measurements. Those skilled in the art will appreciate thatany number of techniques may be employed to measure heart ratevariability based on relatively shorter periods of time.

Referring still to control algorithm of FIG. 6, once the heart ratevariability is determined, the system monitors, at step 620, whether theheart is operating within its normal parameters as illustrated in FIG. 5by the solid lines in the graph. If it is determined that heart ratevariability is too high or too low relative to the IHR for that timeperiod, the stimulation of the vagus nerve 60 is adjusted to bring theheart into its normal heart rate variability parameters. If the heartrate and/or heart rate variability are maintained within their normalpatterns, then no changes to the stimulation are made.

The determination of step 620 can be made in any number of ways. It maybe made based on IHR measurements, or heart rate variabilitymeasurements, or both. For example, if more than a 10% change occurs inthe median IHR rate between the “off” and “on” segments, then anadjustment to the vagus nerve stimulation should be made. As anotherexample, if the summed standard deviation values for 3-5 consecutive IHRmeasurements exceeds a certain number, then the stimulation of the vagusnerve 60 needs to the adjusted. So if the standard deviation is measuredto be at least 4 at the IHR of 80 (being above the 90th percentile fourtimes in a row) for 3 consecutive IHR measurements, then it is clearthat the heart rate variability is not normal and the vagus nervestimulation needs to be adjusted or simply turned off. Those skilled inthe art will appreciate that any number of criterion such as these maybe established to determine when the heart is not operating in itsnormal fashion. The system 10 may monitor variability so that it is nottoo high or even too low. In addition, the system 10 may have memory fora learning capability such that it can learn the heart rate variabilitycharacteristics during normal operation of the specific patient'sindividual heart and the decision-making criterion of step 620 may beadjusted accordingly. Further, the physician may adjust the parametersfor when the vagus nerve stimulation needs to be adjusted to account forthe specific needs of each individual patient.

At step 625, if it is determined that the vagus nerve stimulation needsto be adjusted, any number of approaches may be taken. One option isthat the patient may be alerted by an audio signal or beep to manuallyturn off the stimulation device. The audio signal may alternatively be astimulation device that provides sensory stimulation, or a vibratingmechanism similar to a pager. Another option is to automatically turnoff the stimulation provided to the vagus nerve 60. A third option is toadjust the stimulation by adjusting the pulse frequency, amplitude,and/or width (discussed further herein). A fourth option is to providesignaling to a pacemaker to maintain the heart rate at a desired level(discussed further herein).

In the event that it is determined that the heart rate variability istoo low, then stimulation can be altered to increase variability.Similarly, if the variability is too high, stimulation can be altered todecrease variability. The VNS may be set to provide a stimulation cycle.It is desirable to utilize the law of independent conduction, discussedabove, when providing the electrical stimulation. In particular,depending upon the parameters to be used, can stimulate different fiberwidths.

As discussed above, specifically targeting certain tissue types withinthe VNS can be beneficial in minimizing the side-effects of the VNS. Assuch, the VNS may be set to stimulate selectively slow conducting vagalnerve fibers using appropriate stimulation parameters which include butare not limited to delivering saw-tooth shape anodal pulses. Selectionof parameters such as time of exponential decay, frequency ofstimulation, length of stimulation, interstimulus interval, etc. canthen be optimized for each individual.

Another possibility to achieve the desired heart rate or heart ratevariability is to make use of certain periods of time when the VNS is“off”. Referring to FIG. 7, a chart is shown of the IHR of a patient asa function of time. Time period 0 through 37.7 reflects the periodduring which the VNS is turned “on”. The time periods g1 through g5reflect time periods when the stimulator resets itself and nostimulation is delivered to the vagus nerve 60. Thus, though these “offgaps” are due to certain aspects of the VNS and are thereforeundesirable, they may be useful to achieve the desired heart rate orheart rate variability.

FIG. 8 depicts another embodiment of the present invention having apacemaker 40 or like device implemented to affect the heart 55 in theevent that vagus nerve 60 stimulation causes the heart 55 to beatoutside of the acceptable ranges. The pacemaker 40 may control the heartrate and/or may be variable for a period of time during which the vagusnerve 60 is being stimulated. As such, pacemaker 40 is coupled via alead or telemetry to signal generator 20. The pacemaking parameters maybe preset and adjustable by the physician and further adjustable so thatthe pacemaker 40 maintains heart rate parameters that existed justbefore the vagus nerve stimulation device was turned “on”. Pacemaker mayinclude a processing circuit similar to that of FIGS. 3 and 4 to providevariable pacing of the heart and for processing of any sensor signal.This embodiment may be preferred in the event that the adjustment of thevagus nerve stimulation (embodiment discussed above) reduces theefficacy of avoiding the onset of a seizure. In this regard, the presentinvention may be incorporated for example within rate responsivepacemakers as disclosed in U.S. Pat. Nos. 5,052,388 and 5,562,711 andcommercially available pacemakers sold by Medtronic, Inc. under thetrademarks KAPPA® and LEGEND ELITE®. These patents and pacemakers areincorporated herein by reference in their entireties.

In another embodiment, both of the above embodiments are combined suchthat adjustments are made to the vagus nerve stimulation parameters andalso the pacemaker 40 to maintain the heart within a desired rate andvariability. The signal generator 20 and pacemaker 40 may be packaged ina single implantable casing, may be coupled via a cable, or maycommunicate via telemetry.

FIG. 9 discloses yet another embodiment of the invention where apacemaker is equipped with a digital signal processing algorithm torecognize whether the vagus nerve 60 is being stimulated. The pacemakermay provide the necessary pacing of the heart in the event that thealgorithm senses that the vagus nerve 60 is being stimulated, shownbelow. The pacemaker may also serve to maintain the heart rate at safelevels in the event that the patient does experience an epilepticseizure. FIG. 10 is a block diagram of an exemplary algorithm fordetecting VNS-induced artifact in the EKG signal to determine when thedevice is performing vagal nerve stimulation. At 700, the analog EKGsignal is digitized (preferably with 240 Hz sampling and 10 bits ofprecision). At 705, the digital EKG signal (y(k), k=1, 2, 3, . . . ) isthen passed into a first order statistic filter (preferably a medianfilter of order 0.0625 seconds, i.e., 15 data points at 240 Hz samplingrate). At 707, the input to and output from this filter are thenadjusted for any filter-induced phase lag and the difference is computedand rectified using the absolute value. Specifically, a signalrepresented by the following formula is computed at each point in time:e(k)=|y(k)−median(y(k−7), y(k−6), y(k−5), . . . , y(k), y(k+1), y(k+2),. . . , y(k+7))|,for k=8, 9, 10, . . . . At 715, the e(k) sequence is then passed into asecond order statistic filter (preferably of order ⅓ second, i.e., 81data points at 240 Hz sampling rate). The output of this filter isdenoted as fg(k) and is referred to as the foreground sequence. At 720,this output is sampled every 2 second (i.e. decimated by a factor of120) and at 725 passed through a third order statistic filter of order 2minutes (i.e., of order 240) to produce a moving background sequence,bg(k). This background sequence is held constant between updates and, at730, the ratio R(k)=fg(k)/bg(k) is computed for each point in time(every 1/240th of a second). At 735, this ratio sequence is comparedagainst a threshold value (preferably about 5), and the systemdetermines that the stimulation is “on” when R(k). 5 and “off” whenR(k)<5. FIG. 11A is a graph showing a raw EKG signal with the VNSartifact on the left side. FIG. 11B is another graph showing thedifference between the raw signal and the output of the first medianfilter 705. FIG. 11C is another graph showing the output ratio R(k)(from the divider 730) and the threshold of 5 to determine when thedevice is “on” or “off”. As can be seen in this graph, the VNS is “on”at roughly time t=5 seconds through t=41 seconds. Known periodicities ofthe VNS device can be compared with the detected on times to verifywhether the VNS is operating in accordance with a desired schedule andstimulation parameters. Accordingly, under this embodiment, the presentinvention may be implemented to modify a pacemaker that can be used withexisting VNS devices or with VNS devices of the present invention.

In another embodiment of the present invention, vagus nerve stimulationmay be provided during periods when heart is not vulnerable to stoppage.This can be achieved by sending single pulses and measuring the phaseresetting effect on the heart EKG. This will enable us to identify thephase that has the least effect on the heart. Thus, the signal generator20 may be programmed to trigger only when the cardiac cycle is lessvulnerable to stoppage or the part of the cycle when the stimulation hasthe lowest effect on the heart. This testing can be done by physician inclinic during or after implant or it may be programmed to automaticallyperform within the signal generator 20. See Jalife J, Anzelevitch C.,“Phase resetting and annihilation of pacemaker activity in cardiactissue,” Science 206:695-697 (1979); Jalife J, Antzelevitch C.,“Pacemaker annihilation: diagnostic and therapeutic implications,” AmHeart J 100:128-130 (1980); and Winfree A T., “Sudden cardiac death: Aproblem in topology,” Sci Am 248:144-161 (1983).

In yet another embodiment of the present invention, vagus nervestimulation is provided to enhance desynchronization of the EEG rhythms.Desynchronization of EEG (i.e., to achieve an EEG that has relativelylow amplitude and relatively high frequency) reduces the probability ofseizure occurrence. Accordingly, it is desirable to find the parametersof the VNS stimulation that will optimize the EEG desynchronization.Referring again to FIG. 2, EEG electrode 30 may provide feedback tosignal generator 20 so that it can responsively alter the stimulationpulse parameters to induce an EEG having a generally low amplitude andhigh frequency. Since the EEG characteristics of each patient may vary,testing may be done on the patient of varying stimulation pulses toobserve the effects on the EEG. In addition to performing this duringimplant, this can also be performed periodically or when the patient issleeping.

In another embodiment of the present invention, the heart may bemonitored for real-time changes in EKG for the detection of seizures andautomated triggering of VNS. Seizures originating from or spreading tobrain areas involved in cardiovascular regulation, cause changes inheart rate, R-R variability and blood pressure. The heart can thereby bymonitored for these changes that are indicative of the occurrence of aseizure. Specifically, the changes in the heart rate that may indicate apossible onset of a seizure include non-exertional increases in heartrate, decreases in heart rate, increases in R-R variability, decreasesin R-R variability, etc. These patterns may also be learned over time asthe patient experiences seizures, the sensor Automated detection ofthese changes in accordance with the present invention can be also usedto turn on the VNS, if it is safe to do so. If the EKG changes occurringduring seizures are considered dangerous, the VNS may be turned off ormodified to minimize the risk of an adverse reaction. Further, this EKGalgorithm can also be used to warn the patient or those around thepatient that of abnormal heart function so that the patient may actaccordingly to minimize the risk of sudden unexpected death which iscommon among persons with intractable epilepsy. Accordingly, heart EKGmay be monitored by a signal generator system and/or a pacemaker systemand may be incorporated within those embodiments of FIGS. 2, 8 and 9.

By using the foregoing techniques for electrical stimulation of thevagus nerve 60, epilepsy can be controlled or prevented with minimizedeffects on the heart. Those skilled in that art will recognize that thepreferred embodiments may be altered or amended without departing fromthe true spirit and scope of the invention, as defined in theaccompanying claims.

1. A system for controlling operation of a heart comprising incombination: (a) at least one sensor capable of measuring acharacteristic of the heart indicative of an occurrence of a seizure,the sensor being capable of measuring R-R variability, (b) means forprocessing the measured characteristic to determine whether there is apossible occurrence of a seizure; and (c) an implantable pacemakercoupled to the at least one sensor to regulate the operation of theheart in response to the characteristic measured by the at least onesensor.
 2. The system of claim 1, wherein the sensor is capable ofmeasuring a heart rate of the heart.
 3. The system of claim 1, whereinthe sensor is capable of detecting a QRS complex.
 4. The system of claim1, wherein the sensor is capable of detecting an R-wave.
 5. The systemof claim 1, wherein the sensor is capable of measuring blood pressure.6. The system of claim 1, wherein the sensor is capable of measuring arelationship between heart rate and heart rate variability.
 7. Thesystem of claim 1, wherein the characteristic of the heart is indicativeof a serious or life-threatening state.
 8. The system of claim 1,further comprising: (d) an implantable signal generator providingstimulation energy; and (e) at least one electrode having a proximal endcoupled to said signal generator and a distal end adapted to providestimulation to a vagus nerve of a patient.
 9. The system of claim 8,wherein operation of a heart may be controlled by altering thestimulation energy provided to the vagus nerve.
 10. The system of claim1, wherein the sensor provides indication of vagus nerve stimulation andfurther comprising: (d) a control algorithm responsive to the sensor foractivating the pacemaker to regulate the heart.
 11. The system of claim1, wherein the sensor provides indication of vagus nerve stimulation andfurther comprising: (d) a control algorithm responsive to undesirableheart activity resulting from vagus nerve stimulation to shut down ormodify the vagus nerve stimulation.
 12. The system of claim 1, whereinthe sensor provides indication of vagus nerve stimulation and furthercomprising: (d) a sensory stimulus responsive to the sensor for alertingthe patient of an undesired effect on the heart from the possibleoccurrence of the seizure.